Immune system inherently has a role of recognizing and eliminating a foreign body such as bacterium or virus which is different from the self but, sometimes, it excessively reacts with one's own normal cells and tissues and attacks them due to congenital or acquired abnormality. Autoimmune disease is a general name for the diseases resulted by such a state. Among them, a disease caused by the reaction of autoantibodies (antibodies which recognize one's own cells and tissues as an antigen) with autoantigen (one's own cells and tissues) is called “autoimmune disease of autoantibody type”. Examples of the autoimmune disease of autoantibody type include myasthenia gravis, hemolytic anemia of autoimmune type, idiopathic thrombocytopenic purpura, neutropenia of autoimmune type, hyperthyroidism or Hashimoto disease caused by anti-TSH antibody, acute encephalitis of autoantibody type, and non-herpetic marginal encephalitis.
As to a treating method for autoimmune disease of autoantibody type, administration of steroidal agents or immunosuppressants has been conducted frequently. However, any of those drugs does not specifically suppress the autoantibodies which are fundamental cause of the disease but generally suppress the immunoreaction as a whole. Therefore, the drugs have no specificity and the methods are not a sufficiently effective treating method in terms of QOL (Quality of Life).
With regard to myasthenia gravis which is one of the representative examples of the autoimmune diseases of autoantibody type, there is no already-known treating agent for the fundamental treatment therefor as well but merely the above steroidal agents, the above immunosuppressants, cholinesterase inhibitors, plasma exchange therapy, immunoglobulin preparations for intravenous injection, and thymectomy have been mostly used (cf. Trends of clinical test studies for myasthenia gravis, Nippon Rinsho, Vol. 66, No. 6, pp. 1155-1157; High-dose therapy by immunoglobulin, Shinkei Chiryo, Vol. 25, No. 6, pp. 689-692; “Guideline for the Treatment of Myasthenia gravis (MG)”, Report of 1995 by the Search and Study Team for Special Diseases and Immunological Neural Diseases, Health and Welfare Ministry; “Current Status of Treatment and Prognosis of Myasthenia Gravis in Japan”, Memorial Lecture at the Fourth MG Forum).
Among the above, the use of choline esterase inhibitors is difficult for its dose setting. Also, it may be sometimes necessary that atropine sulfate is intravenously injected or airway is secured taking the case of side effect into consideration. Moreover, when high dose is administered for a long period, its effect lowers and, in some cases, cholinergic crisis may happen, which are regarded as problematic. This agent is not intended for the therapeutic treatment but is a mere symptomatic treatment. Fundamentally, the minimum dose by which the effect is achieved is to be used and a long-term administration is to be avoided if at all possible.
With regard to steroidal agents, their side effect is regarded as problematic and control of the side effect is very important. In addition, a continued administration of such agents for a long period is difficult and it is necessary to control together with the use of nonsteroidal immunosuppressants such as tacrolims or cyclosporine. However, as mentioned already, the above agents are for mere symptomatic treatment and are not fundamental therapeutic means.
With regard to thymectomy, although it shows some effect, there are problems of anxiety of patients to excising operation and also of cost. There is another problem that it is not applicable to small children whose immune function is still undeveloped and to patients suffering from immunodeficiency disease. In addition, although it exhibits some effects, long years of up to units of ten years are required until the effect is confirmed. It is unavoidable that other symptomatic treatments are jointly conducted until the effect is acknowledged. There is still another problem that the effect was confirmed for only less than 50% of the patients.
With regard to plasma exchange therapy, a cost of as high as not less than one million yen is needed for one treatment. A subsidy for the medical expenses of myasthenia gravis according to the system for Diagnosis Procedure Combination is only about six hundred thousand yen whereby the burden at the medical care site is big. Further, there is a problem that duration of the effect thereof is as short as only about one month.
As a treating method for myasthenia gravis, effectiveness of gamma-globulin preparations have been confirmed in recent years and some pharmaceutical manufacturers are now conducting clinical tests therefor. However, since gamma-globulin preparations are biological preparations derived from human plasma, there may be a risk of infection due to unknown virus, etc. In addition, dose of the gamma-globulin preparations is high (400 mg/kg, continued administration for 5 days) and, it is expected that burdens for patients and medical care sites will be considerably high. On the other hand, duration of the effect thereof has been said to be the same as plasma exchange therapy or merely a bit longer.
To sum up, the problem in the treatment of myasthenia gravis is that, as to the treatment using low-molecular drug, it is a mere temporary symptomatic treatment and, as to plasma exchange therapy, gamma-globulin preparations and thymectomy, the problems in terms of effect and cost are still left as well.
In view of the above problems, the present inventors thought that an effective effect will be expected in a small dose causing no burden to patients if an antibody reacting only to an anti-acetylcholine receptor autoantibodies which have been believed to be a cause of myasthenia gravis can be prepared in recombinant protein. Then the present inventors prepared fusion protein of nAChRα1 subunit N-terminal extracellular region with antibody heavy chain constant region as a substitute for antiidiotype antibody in order to neutralize the anti-acetylcholine receptor autoantibodies. Since this fusion protein has the activity of neutralizing the autoantibodies and also injuring the autoantibody production cells, it has been judged to be very effective to myasthenia gravis which is one of autoimmune diseases of autoantibody type. However, this fusion protein had a low expressing amount and its industrial production was under a difficult state (cf. Japanese Patent No. 4495776).